Lynch syndrome (LS) is a genetic disease predisposing to colorectal cancer (CRC) that affects more than one million Americans. Germline mutations in DNA mismatch repair (MMR) genes, primarily MLH1 and MSH2, cause deficient DNA mismatch repair (dMMR) and LS. LS CRCs have exceptionally high numbers of small insertion/deletion frameshift and missense mutations. Elevated dMMR mutation rates cause some mutations to recurrently arise in tumors from different patients. For example, the human TGF?R2 gene has a poly(A) coding repeat, and the same ?shared? frameshift mutation is recurrently identified in >60% of LS dMMR CRCs. Here, we will use state of the art tools to systematically delineate recurrent LS mouse and human pre-malignant neoantigens, test whether vaccination with frequently mutated ?shared? immunogenic neoantigens reduces LS mouse CRC penetrance, and elucidate adaptive immune mechanisms for CRC immunoprevention. In Aim 1 we will comprehensively delineate frequently mutated recurrent neoantigens in Lynch syndrome mouse colorectal mucosa and adenomas. This will provide insights into pre-malignant colon dMMR immunoediting mechanisms, the timing and sequence of dMMR neoantigen appearance, and systematically delineate the most immunogenic recurrent shared dMMR neoantigen vaccine targets for LS mouse CRC immunoprevention. In Aim 2 we will test the hypothesis that recurrent neoantigen vaccination reduces mouse Lynch syndrome mismatch repair deficient epithelial cells in colon mucosa. This will give insights into the mechanism of dMMR colon mucosal immunoediting, and test the efficacy and safety of a dMMR recurrent neoantigen vaccine strategy using the earliest neoantigen mutations for LS immunoprevention. In Aim 3, we will test the hypothesis that recurrent neoantigen vaccination reduces mouse Lynch syndrome colorectal tumor burden. This will evaluate the efficacy and safety of a dMMR recurrent adenoma neoantigen vaccine strategy for Lynch syndrome immunoprevention and provide insights into the mechanisms of dMMR immunoediting. Finally, in Aim 4 we will systematically delineate Lynch syndrome patient adenoma recurrent neoantigens. This will delineate the most promising candidate recurrent neoantigens that can be used for LS patient tumor vaccine clinical trials and give insights into dMMR immunoediting mechanisms. Our overall goal is to develop effective, safe mechanism based neoantigen vaccination strategies for Lynch syndrome CRC immunoprevention.